Salt-loving microbe forges its own path

The announcement of a third metabolic pathway raises possibility that there are more to be found.

The discovery in a hardy microbe of a novel way of processing carbon1 shows that there are more ways for organisms to sustain life in the harshest of environments than previously thought.

The breaking down of carbon compounds into basic building blocks is the daily grind of living organisms. Vertebrates use a
metabolic process known as the Krebs cycle, in which the molecule acetyl coenzyme A (acetyl-CoA) has a crucial role, helping
to usher compounds from one enzyme to the next as they are dismantled. Vertebrates cannot convert acetyl-coA into the components
necessary to make glucose, but plants and some bacteria, fungi and microorganisms can.

Two alternative pathways have been described by which microorganisms, including ancient bacteria, convert acetyl-CoA into
the building blocks of sugar — the glyoxylate cycle and the ethylmalonyl-CoA pathway. The latter was discovered just four
years ago2.

Now, a research team based in Germany has found that a microbe that thrives in salty settings — it lives in the Dead Sea in
the Middle East — uses a third method, the methylaspartate cycle.

The breakthrough began with the realization that the microorganism, Haloarcula marismortui, which belongs to the domain Archaea, couldn't be using the glyoxylate cycle because it lacked an essential enzyme called
isocitrate lyase. But H. marismortui couldn't be using the ethylmalonyl-CoA pathway either, the researchers noted, because it doesn't have all of the genes required
to synthesize the necessary enzymes. "We thought it would be interesting to study this organism in detail because it seemed
like a new pathway," says Ivan Berg, a microbiologist at the University of Freiburg in Germany and one of the paper's authors.

Berg and his colleagues spent more than two years analysing the enzymes used by H. marismortui when it was cultivated on acetate1. The analysis yielded the discovery of the methylaspartate cycle, a more lengthy pathway that allows the microbe to thrive
in harsh salty conditions. Indeed, the complex nature of the process, named for the cycle intermediate methylaspartate, offers
advantages to a microbe exposed to the Dead Sea's unusual conditions. For example, one of the cycle's intermediate compounds
limits the effects of osmosis — the movement of water across a membrane to balance salinity on both sides. This is a handy
survival tool in such a salty environment.

More to come

William Martin, a botanist who researches cellular evolution at the Heinrich Heine University in Dusseldorf, Germany, calls
the discovery "a major advance in our understanding of the biochemical world".

And the discovery of a third metabolic pathway is not only a step forwards, but also an indication that others may be awaiting
identification. "It really showcases how there's a lot to be learned about metabolism," says Scott Ensign, a biochemist at
Utah State University in Logan and the author of a perspective that accompanies the Science paper. "It means there are probably other pathways out there for acetate assimilation."

Berg too says he expects more routes to be uncovered. "The diversity of life is bigger than we know now," he says.

The research may also offer evolutionary insight. In analysing the enzymes that propel the methylaspartate cycle, the authors
found striking similarities to enzymes identified in ancient bacteria, an indication that H. marismortui grabbed the genes needed for the cycle by lateral gene transfer. This suggests 'evolutionary tinkering' — instead of evolving
through a long process of random mutations, the organism did so, at least in part, by borrowing genetic code. And in this
case, the researchers say, that connection is quite clear.

"There are not too many examples where we can more or less surely say how the pathway evolved. In this case it seems to be
quite exciting," Berg says. "This pathway is kind of a wonder."